5- Hydroxy tryptamine

TRYPTAMINE, 5-HYDROXY-N,N-DIMETHYL INDOL-5-OL, 3-[2-(DIMETHYLAMINO)ETHYL] 5-HYDROXY-N,N-DIMETHYLTRYPTAMINE 3-(2-DIMETHYLAMINOETHYL)INDOL-5-OL N,N-DIMETHYLSEROTONIN BUFOTENINE MAPPINE... 

Pictet-Spengler syntheses of tryptamines containing hydroxy group at N atom of the side chain, and their transformation to tri-, tetra-, and pentacyclic systems related to eudistomins 98H(49)499. 

Michael addition reaction of 1-hydroxytryptamines to Q ,/3-unsaturated carbonyl compounds is worthy of note (99H2815). Addition of Ab-acetyl- 1-hydroxy-tryptamine (39) to methyl acrylate and methyl crotonate in the presence of... 

In the reaetion of 1-alkoxytryptamines with aqueous HCl, 5-ehlorotryptamines (213), 7-ehlorotryptamines (214), and dealkoxylated tryptamines (53) are pro-dueed, and the results are summarized in Table V. Interestingly, the 1-substituent is an important faetor in governing the yield of 5-ehlorotryptamines (213). As the substituent ehanges in turn from hydroxy to methoxy, l-(2-methoxyearbonyl)ethoxy, and l-(2-methoxyearbonyl-l-methyl)ethoxy groups (entries 1-4), the yield of 213a inereases dramatieally. 

Treatment of 1-hydroxy-iVb-trifluoroacetyltryptamine (48), which is readily available in three steps from tryptamine (259, Scheme 40), with MsCl in THF in the presence of indole (3 mol eq) and EtsN produces l-trifluoroacetyl-1,2,3,8-tetrahydropyrrolo[2,3-(j]indole (49c, 25%), l-trifluoroacetyl-3a-(4-chlorobutoxy)-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (52c, 6%), iVb-trifluoroacetyl-6-mesyloxytryptamine (50c, 8%), 3a-(indol-2-yl)- (260, 5%), and 3a-(indol-3-yl)-l-trifluoroacetyl-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (261, 12%). In this reaction, solvent plays an important role. Among the tested solvents such as benzene, CHCI3, 1,2-dichloroethane, THF, DMF, CH3CN, and iV-methylformamide, CHCI3 is found to be the solvent of choice to provide a 21% yield of 261. The use of excess indole (10 mol eq) further raises the yield to 30%. 

Biogenic amines. A general term usually used to describe endogenous amine-containing compounds such as dopamine, 5-hydroxy-tryptamine, and norepinephrine that function as neurotransmitters. 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Cox, B, Lee, TF and Martin, D (1981) Different hypothalamic receptors mediate 5-hydroxy-tryptamine and tr5 ptamine induced core temperative changes in the rat. Brit. J. Pharmacol. 72 472-482. 

Hydroxy tryptamine, or serotonin, is a neurotransmitter in the central nervous system (CNS). The nerve-cell bodies of the major serotoninergic neurones are in the midline raphe nuclei of the rostral pons, and ascending fibers innervate the basal ganglia, hypothalamus, thalamus, hippocampus, limbic forebrain, and areas of the cerebral cortex. The serotoninergic system plays an important role in the control of mood and behavior, motor activity, hunger, thermoregulation, sleep, certain hallucinatory states, and some neuro-endocrine mechanisms. 

Commissaris, R. L., Lyness, W. H., Moore, K. E., and Rech, R. H. (1981) Central 5-hydroxy-tryptamine and the effects of hallucinogens and phenobarbital on operant responding in rats. Pharmacol Biochem. Behav., 14 595-601. 

Psilocin has also been the object of considerable investigation using animals as subjects. Much of the initial work with psilocin, as well as other 4-hydroxy-tryptamine derivatives with alterations in the side chain and/or terminal amine, was performed at Sandoz Laboratories in Switzerland (29,245). Subsequent investigations have shown that psilocin produces hyperthermia in rabbits (113), induces the head-twitch in mice (43), disrupts acquisition of avoidance behavior in rats (240), increases startle response magnitudes in rats (68), increases limb-flick behavior in cats (120), and produces discriminative stimulus effects in rats similar to those of 5-OMeDMT (59) (93). 

The 5-hydroxy derivative of DMT, bufotenine, or N,N-dimethyl-serotonin, is another naturally occurring tryptamine found to occur in South American snuffs. Intravenous administration of bufotenine (53) was reported by Fabing and co-workers (59,60) to be hallucinogenic in man. This finding is in conflict with a later report by Turner and Merlis (235). Apparently, due to its low lipid... 

Gessner, P. K., Godse, D. D., Krull, A. H., and McMullan, J. M. (1968) Structure-activity relationships among 5-methoxy-N,N-dimethyltryptamine, 4-hydroxy-N,N-dimethyltryptamine (psilocin) and other substituted tryptamines. Life Sci., 7 267-277. 

Figure 13.28 A possible mechanism by which increased levels of tryptophan and/or tyrosine can occur in neurones and lead to fatigue. The mechanism proposes that physical activity increases the entry of tryptophan or tyrosine into the neurones which increases the concentration of the neurotransmitters, 5-hydroxy-tryptamine or dopamine, respectively. The neurotransmitters are present in vesicles in the presynaptic terminal (Chapter 14). (The pathways for the formation of 5-hydroxytryptamine and dopamine are described in Chapter 14.) This enhances the amount release into the synapses which decreases the excitation of 5-hydroxytryptamine or dopamine neurones in the motor control pathway. It is assumed that they are inhibitory neurotransmitters, they will reduce electrical activity in the motor control pathway and hence nervous stimulation of muscle fibres. This results in fatigue. Mechanisms by which physical activity might result in increased entry of these amino acids into the brain are presented in Appendix 13.5.

MAO is a much less discriminating enzyme in that it will catalyze the removal of an amine group from a variety of substrates. The action of MAO on norepinephrine and epinephrine also is indicated in Figure 9.5. The list of its substrates is very large, including endogenous substances (norepinephrine, epinephrine, dopamine, tyramine, 5-hydroxy-tryptamine) and many drugs that are amines. At least in the brain, two separate forms of MAO have been described MAO type A and MAO type B. The two types are differentiated on the basis of substrate and inhibitor specificity. 

Fig. 1. Influence of substituents in the aromatic ring on the selectivity of 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives as monoamine oxidases (MAO) A or B inhibitors. Ratio of selectivity was calculated from IC50 values of MAO A and B determined by an in vitro assay of mouse brain mitochondria using 5-hydroxy tryptamine (5-HT) and 2-phenylethylamine (PEA) as specific substrates, respectively (see Ref. [9]). Smaller values indicate that inhibitors are MAO A selective [71].

Bel N, Artigas F Fluvoxamine preferentially increases extracellular 5-hydroxy-tryptamine in the raphe nuclei an in vivo microdialysis study. Eur J Pharmacol 229 101-103, 1992... 

Back to the metabolism discussion. And to the search for the actual drug, the magic bullet, that actually precipitated a model schizophrenic state. If one were to find it, one could look skillfully for the counterpart in the human animal, the one that simply appeared on the scene from some mismanaged metabolic process, and thus could be blamed for mental illness. It had been observed that the longer the chains on the N,N-disubstituted tryptamine, the less the potency. And the longer the chains, the less of the drug was excreted as the 6-hydroxyl metabolite. This focused attention on the hydroxy metabolites of the two simplest and most potent of the dialkyltryptamines, DMT and DET. 

Two obstacles effectively prohibit this availability. Serotonin has a free hydroxy group (the 5-hydroxy which is the H of 5-HT). This is a big polar water-loving pimple which denies it any passage across the brain s defensive Maginot Line, the blood-brain barrier. And there is the second problem. There is a exposed amino group, the amine of T of 5-HT, the tryptamine, which is immediately removed by the body s monoamine oxidase enzyme. In short, it is blocked from entry into the brain because it is both too polar and too metabolically fragile. 

---